Depression is a prevalent mental illness contributing significantly to morbidity. To decrease this substantial public health burden, focus on reducing risk and first incidence of depression during adolescence is a priority. This project, which will innovatively combine risk factor research and evidence-based prevention programs, will advance knowledge on personalized approaches to prevention that may be able to better bend trajectories of depression that surge throughout adolescence. The primary goal of this collaborative R01 study is to examine whether the effects of depression prevention programs can be maximized by matching youth with theoretically-based risk profiles to interventions that fit their needs. This two site study will randomly assign adolescents with high cognitive and/or interpersonal risk to two preventive interventions that are designed to address distinct risk factors for depression: Coping with Stress (CWS), a cognitive behavioral program, and Interpersonal Psychotherapy-Adolescent Skills Training (IPT-AST), an interpersonal program. We will base these matching profiles on pre-prevention data from a well-characterized sample of youth whom we have been following as part of a collaborative multi-wave naturalistic study to predict developmental trajectories of depression (NIMH 5R01 MH077195/MH077178; Hankin and Young, PIs). We will include adolescents, from the original 3rd and 6th grade cohorts, who will be in 7th and 10th grades for this proposed prevention trial. A total of 210 participants across two sites, University of Denver and Rutgers University, will be stratified on cognitive and interpersonal risk and randomized to the two prevention conditions. Independent evaluators will assess participants at baseline, mid-intervention, post-intervention and follow-up (every 6 months up to 36 months post-intervention). The goals of the study are to (1) demonstrate that prevention programs can modify depression trajectories among youth by examining within person changes in trajectories over time (three years before and three years after the prevention programs) and by comparing trajectories of prevention youth with changes in same aged cohorts; (2) evaluate a personalized prevention approach to bending depression trajectories by matching and mismatching youth to either CWS or IPT-AST based on individual risk profiles; (3) examine mechanisms of bending depression trajectories and test whether the prevention programs operate via their hypothesized processes; and (4) explore how genetic susceptibility, emotion regulation, and temperament may affect individual response to IPT-AST and CWS. By implementing evidence-based prevention programs after 3-years of prospective naturalistic data collection, this study will contribute essential data on personalized medicine and altering developmental trajectories of first-onset depression.